ABSTRACT Halting tuberculosis (TB) transmission will be most efficiently achieved by focusing control efforts on sites of high transmission and by developing new drugs and vaccines that target bacterial transmission. We hypothesize that household TB transmission is dramatically under-estimated because mixed infections are common and secondary cases may be infected by minor populations having a transmission advantage; ergo that mismatch between the Mycobacterium tuberculosis (Mtb) strain isolated from the index case and secondary case does not preclude household transmission. We also hypothesize that the host immune and pathological response to Mtb isolates and the ability of different Mtb isolates to survive the stress of aerosolization strongly impacts transmission potential. Here, we propose to study characteristics of TB transmission within households, the bacterial isolate and its interaction with the host innate and adaptive immunity that aid or are permissive of transmissibility. To address these hypotheses, we will conduct retrospective and prospective cohort studies in Brazil and in Uganda leveraging over a decade of household contact studies in Brazil (2004-date) funded by the International Collaboration for Infectious Diseases Research (ICIDR) and the Tuberculosis Research Unit (TBRU), and over 20 years of collaborative research among our study team. Our Specific Aims are: 1) To determine the extent to which household transmission is responsible for co-prevalent and incident TB cases that initially appear to be genetically distinct from index cases within the same household. 2) To investigate the in vitro immune phenotype of transmitted versus not-transmitted Mtb isolates in Brazilian and Ugandan households stratifying for HIV status. 3) To characterize the innate and adaptive immune response in persons with known household exposure to high and low transmission isolates and the impact of HIV infection. 4) To identify the component of Mtb genes that aid in bacterial survival in aerosols. 5) To investigate the bacterial factors underlying divergence in the host response to high and low transmission isolates. Together, these studies will provide new paradigms for transmission and novel targets for intervention.